Alkane bis quaternary ammonium salts



Patented Oct. 17, 1950 UNITED STATES PATENT OFFICE ALKANE BIS QUATERNABYAMMIONIUM SALTS Peter L. de Benneville, Philadelphia, Pa., and

Richard W. Gormly, Collingswood, N. J., assignors to Rohm 8.: HaasCompany, Philadelphia, Pa., a corporation of Delaware No Drawing.Application June 29, 1949,

Serial No. 102,146

4 Claims. (Cl. 260-567.!

CH; CH: CH: CH:

(Da r o wherein R is an'alkyl group of seven to nine carbon atoms, A isan alkylene chain of two to four carbon atoms, and X is chlorine orbromine. The compounds thus defined have powerful bactericidal andfungicidal actions.

Bis quaternary ammonium salts in which the two nitrogen atoms areseparated by an alkylene group and in which the nitrogen atoms carrylong chained alkyl groups have been reported. These compounds have aboutthe same order of bactericidal efliciency as mono quaternary salts ofcomparable constitution in some cases, and in others, less. As comparedwith either of these types of quaternaries, the compounds of the presentinvention are markedly more effective and efficient in controllingbacteria and fungi.

The bis quaternary ammonium halides of this invention are prepared byreacting together in a molar ratio of about one to two abis(dimethylamino) alkane, the alkane group having a chain of two tofour carbon atoms between nitrogen atoms, and an alkylbenzylhalideinwhich the alkyl group has seven to nine carbon atoms. The two reactantsmay be directly combined or they may be reacted by addition in thepresence of an inert organic solvent such as benzene, toluene,

where R is an alkyl group of seven to nine carbon atoms. The conditionsfor effecting this reaction are essentially the same as described abovefor the reaction of an alkylbenzyl halide and atetramethylalkylenediamine.

Preparation of bisldimethylamino)alkanes follows known procedures ofreacting a dihaloalkane with dimethylamine. There are thus available1,2-bis(dimethylamino) ethane, 1,3-bis (dimethylamino) propane, and1,4-bis (dimethylamino) butane, 1,2-bis(dimethylamino) propane, 1,2-bis-(dlmethylamino) butane, and l,3-bis(dimethylamino) butane.

Alkylbenzyl halides having alkyl groups of the required size areprepared in accordance with the method described in our ApplicationSerial No.

xylene, isopropyl alcohol, butyl alcohol, isopropyl 28,274, filed May20, 1948. 'As there described, alkylbenzyl halides are obtained byhalomethylating an alkylbenzene or an alkyltoluene by reaction withanhydrous formaldehyde and hydrogen chloride or bromide in the presenceof a catalyst mixture formed from one molecular proportion of zincchloride and 1.5 to 8 molecular proportions of an aliphaticmonocarboxylic acid of one to three carbon atoms, such as formic,acetic, chloracetic, or propionic. An acid anhydride may be used inplace of those acids or in admixture therewith. Formaldehyde may be usedas a gas or as a revertible polymer. The equivalent of formaldehyde andhydrogen bromide or hydrogen chloride is obtained by use of bromomethylether or chloromethyl ether, which are conveniently prepared by knownmethods and reacted with an alkylbenzene of the required size.

For halomethylation of alkylbenzenes or alkyltoluenes' having alkylgroups of seven to nine carbon atoms from one to 2.5 molecularequivalents of formaldehyde together with 0.75 to 2.5 molecularproportions of zinc chloride taken with 1.5 to Bmolecular proportions ofaliphatic monocarboxylic acid per mole of zinc chloride are used permole 'of an alkylbenzene or alkyltoluene. These components are mixed andstirred at temperatures of 50 to 100 C. and hydrogen chloride or brnmideis passed in. Alternatively, the alkylbenzene and catalyst mixture arestirred together and a halomethyl ether added with observance of thedefined proportions. With a heptyl benzene it is advisable for bestyields to work at the lower end of the temperature range with an upperproportion of monocarboxylic acid within the designated range. Yieldsimprove with increasing size of alkyl group. By this procedure goodyields of alkylbenzyl halides are obtained with introduction almostentirely of a single halomethyl group and without formation 01troublesome resinous products.

For preparation of the alkylbenzyl halides there are requiredalkylbenzenes or alkyltoluenes of the proper size. The exact form of thealkyl group is not important, nor is the orientation of this grouprelative to the halomethyl group or to the methyl group of analkyltoluene of particular significance. The alkyl group may be ofstraight or branched chain structure and may be primary, secondary ortertiary. This group may be introduced by known methods. For example, anacyl halide may be used to introduce an' acyl group into the phenylring, which is then reduced. Olefinic hydrocarbons of the required sizemay be reacted with benzene or toluene in the presence 01' an acidiccatalyst.

The useful starting alkylbenzenes are heptylbenzene, octylbenzene,nonylbenzene, heptyltoluene, octyltoluene, and nonyltoluene in theirvarious isomeric forms. Typical of these are (1- methylhexyl) benzene,(l-ethylpentyl) benzene, (1,3-dimethyl-1-propylbutyl) benzene,(l-methylheptyl) benzene, (2-ethy1hexyl) benzene, (3,5,5-trimethylhexyl) benzene, m-, or p-octyltoluene, p-(l-methylheptyl)toluene, p-(1-ethylpentyl) toluene, (1,3,3-trimethylbutyl) benzene, andthe like. Mixtures of such hydrocarbons may be used as well asindividual alkylbenzenes or alkyltoluenes.

Typical preparations of allrylbenzyl halides follow. Parts shown are byweight.

Example 1.To a mixture of 70 parts of 2- ethylhexylbenzene (preparedaccording to the method of Sulzbacher and Bergmann, J. Org. Chem. 13,303(1948), 50.3 parts of anhydrous zinc chloride, and 60 parts of glacialacetic acid there was added with stirring 42.5 parts of dichloromethylether over the course of an hour, while the reaction mixture wasmaintained at 60 C. Stirring was continued for another two hours withthe temperature held at 60 C. Layer were then allowed to form andseparated. The product layer was washed with sodium bicarbonate solutionand distilled at 110-l25 C./0.07 mm. The distillate corresponded incomposition to 2- ethylhexylbenzyl chloride.

Example 2.-To a mixture of 138 parts by weight of toluene and 90 partsof anhydrous hydrogen fluoride, contained in a copper flask and held at0-10 0., there was added 336 parts of mixed o'ctenes, boiling at 123134C., at such a rate that the temperature did not rise above C. Thereaction mixture was stirred for an hour and then poured upon ice. Theorganic layer was separated, washed with water, with 5% sodiumbicarbonate solution, and again with water, dried over calcium chloride,and finally distilled. Unreacted toluene and octene were removed and theorganic liquid stripped by heating to 115 C./35 mm. There was thenobtained a fraction between 135 C./ 35 mm. and 155 C./0.5 mm. whichconsisted essentially of octyltoluenes.

A mixture was made in the reaction vessel equipped with a stirrer of 32parts of octyltoluene, parts of anhydrous zinc chloride, and 60 parts ofglacial acetic acid. With the temperature kept at 50 to 60 C. there wasadded thereto 20 parts of dichloromethyl ether. The temperature of themixture was then raised to 90 C. for three hours. The reaction mixturewas then separated into layers. The product layer was washed with water,with a 5% sodium bicarbonate solution, and again with water. Upondistillation a fraction was obtained at 133-148 C./0.3 mm. which 4corresponded in composition to 2-methyl-5-octylbenzyl chloride.

Example 3.Commerclal dilsobutyl carbinol was dripped slowly over a bedof alumina at 400 C. The vapors were taken oil and condensed. Therei'romnonene was separated and distilled at 72-75 C./100 mm. The product,

- containing by analysis 85.7% of carbon and 14.3% of hydrogen, was2,6-dimethyl-3-heptene, for which the theoretical content of carbon is85.8% and of hydrogen is 14.3%.

There was added 135 parts by weight of this product to a stirred mixture01' 159 parts of henzene and 147 parts of sulfuric acid. The temperaturewas held between 0 and 10 C. After the mixture had been stirred forthree hours, it was allowed to form layers. The upper layer wasdistilled and the distillate redistilled at 102-l06 C./3 mm. Thisdistillate had a molecular weight of 203 (theory 204) and correspondedin composition to nonylbenzene. The yield was parts.

To a mixture of 80 parts 01' nonylbenzene, 40 parts of zinc chloride,and 59 parts of glacial acetic acid there was added at room temperature45 parts of dichloromethyl ether. The mixture was stirred and heated at70 C. for three hours. It was then allowed to stand and form layers. Theupper layer was separated, washed with hot water, and with sodiumbicarbonate solution, drim over sodium sulfate, and distilled. Thefraction distilling at 141-142 C./2 mm. was nonylbenzyl chloride.

Example 4.To a, mixture of 184 parts of toluene and 103 parts ofsulfuric acid there was added 112 parts of octene while the mixture wasstirred and held at 513 C. The octene had been prepared by dehydrationof capryl alcohol on an alumina, catalyst (cf. Komarewsky, Ulick, andMurray, J. Am. Chem. Soc. 67, 557 (1945)). The reaction mixture wasstirred for three hours at room temperature, and the product layer wasseparated. It was washed twice with concentrated sulfuric acid anddistilled. The fraction taken at 93-95 C./0.3 mm. corresponded incomposition to sec.-octylmethylbenzene.

'To a mixture of 81 parts of this product, 47.5 parts of anhydrous zincchloride, and 65 parts of glacial acetic acid there was added 46 partsof dichloromethyl ether while the mixture was stirred and held at 50-60C. for an hour. It was stirred at 70-75 C. for four hours and allowed toform layers. The upper layer was separated, washed with water and sodiumbicarbonate solution, and distilled. The fraction taken at C./0.3 mm.amounted to 43.8 parts and corresponded in composition tomethyloctylbenzyl chloride.

Example 5.Commercial 3-heptanol was dehydrated on an alumina catalyst at400 C. to yield a mixture of Z-heptene and 3-heptene which was condensedand distilled.

There were mixed 125 parts of this product, 198 parts of benzene, and196 parts of concentrated sulfuric acid while the mixture was stirredand held at 5 C. The mixture was stirred for three hours with thetemperature of the mixture being allowed to advance above roomtemperature. Layers were permitted to form and the upper layer wastaken. It was twice washed with sulfuric acid and distilled to yield 167parts of heptylbenzene, probably a mixture of 2-heptylbenzene and3-heptylbenzene. The product had a carbon content of 87.3% and ahydrogen content of 11.7%, compared with theoretical values distilled.At 127-132' C./2 mm. there was oballowed to stratify and the upper layerwas talreh',

washed with hot water, with a 10% sodium bicarbonate solution. and withhot water, dried over sodium sulfate and distilled. The forerun of 30parts consisted of octylbenzene. There was then obtained at 119-l2l C./1mm. 71 parts of octylbenzyl chloride.

bis (ammonium salt) N,N,N' ,N'-tetramethyl- N,N' bis(octylbenzyl) N,N'ethylene-1,2-bis (ammonium bromide). It had an ionizable bromine contentof 19.1% (theory is 2 3.3%). Against Salmonella typhosa the product asobtained had a phenol coeilicient of 110 and against Staphylococcusaureus one of 665.

Example 10.--A mixture of 40 parts of trimethylene dibromide, 120 partsof p-(l-methylheptyl) benzyldimethylamine, and 250 parts of benzene washeated under reflux for 17 hours. The reaction mixture was stripped ofbenzene by heating under reduced pressure on a steam Example 7.To amixture of 46.5 parts of octylbenzene (chiefly 2-octylbenzene), 1'7parts of anhydrous zinc chloride, and 40 parts of glacial acetic acidthere was added dropwise 50 parts of bis-bromomethyl ether. The mixturewas stirred corresponding in composition to octylbenzyl bromide. Itcontained by analysis 28.8% of bromine. Theory for this product is28.3%.

The following examples illustrate the reaction of alkylbenzyl halidesand tetramethyl diaminoalkanes and also at alkylbenzyldimethylamines andalkylene dihalides to form the his quaternary ammonium salts of thisinvention. Parts shown are by weight.

Example.8.-There were mixed 135 parts of heptylbenzyl chloride, 43.2parts of l,4-bis(dimethylamino) butane, and 250 parts of benzene. Themixture was heated under reflux for three hours and cooled. A colorlessproduct precipitated. It was filtered oil to yield 150 parts of aproduct which corresponded in composition to that ofN,N,N',N-tetramethyl-N,N'-bis(heptylbenzyl) -N,N'-1,4-butylene-bis(ammonium chloride).

- This product has a phenol coeilicient of 350 against Salmonellatyphosa and 750 against Staphylococcus aureus.

The above preparation was repeated with a mixture of p-(l-ethylpentyl)benzyl chloride and p-(l-methylhexyl) benzyl chloride. A similar productwas obtained. It was found to have phenol coeilicients of 330 and 710against Salmonella typhosa and Staphylococcus aureus respectively.

Example 9.A mixture of 123 parts of octylbenzyldimethylamine, 47 partsof ethylene dibromide. and 250 parts of benzene was heated under refluxfor 20 hours. The benzene was distilled from the reaction mixture andthe residue stripped by heating at low pressure. A dark colored,water-soluble, waxy solid was obtained as a residue. It consistedchiefly of the desired bath. There was obtained awaxy solid whichconsisted principally of N,N,N',N'-tetrarnethyl- N,N' bis(p 1methylheptylbenzyl) 1,3 trimethylene-bis(ammonium bromide). The residuehad an ionizable bromine content of 19.1% (theory is 23.0%). Phenolcoeflicients were deter mined of 555 and 570 against Salmonella typhosaand Staphylococcus aureus respectively.

Example 11.-A mixture of '72 parts of 1,4- bis(dimet;hylamino)-butane,238 parts of pa,a, ,-y-tetramethylbutylbenzyl chloride, and 350 parts ofbenzene was heated for three hours under reflux. The benzene wasdistilled ofi under reduced pressure to leave 310 parts of a lightyellow, crystalline solid which had an ionizable chlorine content of10.4%. It corresponded in composition to tetramethyl tert.-octylbenzylbutylene bis(ammonium chloride), the theoretical ionizable chlorinecontent of which is 11.4%.

The phenol coeflicients of this product are 610 and 1300 againstSalmonella typhosa and Staphylococcus aureus respectively. It preventsgermination of spores of Sclerotz'nia fructicola and Macrosporiumsarcinaeforme at concentrations of 0.001%.

Example 12.--A mixture of 50 parts of 1,4- bis-dimethylamino)-butane,177 parts of p- (1,2,4,4-tetramethylpentyl)benzyl chloride, and 300parts of benzene was heated under reflux for four hours. When thereaction mixture was allowed to cool, a crystalline product separated.It was filtered off and dried to yield 190 parts of N,N,N',N'tetramethyl N,N' bis(tetramethylpentylbenzyl) -1,4-butylene bis(ammonium chloride). The ionizable chlorine content was determined as10.6% (theory 11.0%). Phenol coeiiicients of 665 and 1150 were found forthis product against Salmonella typhosa and Staphylococcus aureasrespectively.

In a similar manner parts of decyl'benzyl chloride, 216 parts of1,4-bis-(dimethylamino) butane, 250 parts of benzene were heated toyield 55 parts of solid tetramethyl bis (decylbenzyl) butylenebis(ammonium chloride). This product had a phenol coeflicient of 57against Staphylococcus aureus.

Example 13.-There were mixed 72 parts of 1,4- bis-dimethylamino) butane,283 parts of p-2- octylbenzyl bromide, and 400 parts of toluene.

, The mixture was heated under reflux for three 'alkylgroups of seven tonine carbon atoms, the

halogen having an atomic weight between 35 and 80, are peculiarlypowerful in their bacteriostatic, bactericidal, and fungicidal actions.The above halides may be converted to quaternary salts having anionsother than chlorine and bromine by metathesis. Thus,pentachlorophenates, nitrophenates, acetates, sulfates, and the like maybe prepared.

Preparation of alkylbenzyldimethylamines illustrated by the followingexamples.

Example 14.-(a) To a solution of 8 parts of sodium hydroxide in 30 partsof water there was added 22.5 parts of an aqueous 50% dimethyl aminesolution. The reaction vessel in which this mixture was formed carried arefluxing system cooled with dry ice and acetone. To the mixture therewas added 22.5 parts of heptylbenzyl chloride. The mixture was heated togive gentle refluxing and dimethylamine gas was'slowly passed in duringa period of three hours. The reaction mixture was allowed to form layerswhich were separated. The product layer was washed with water untilneutral to litmus and heated under reduced pressure. There was obtained20 parts of a light yellow oil which had the proper analysis forheptylbenzyldimethylamine.

(b) The procedure of Example 14 (a) was followed with substitution of25.3 parts of nonyl benzyl chloride in place of the 22.5 parts ofheptylbenzyl chloride. There was obtained 18 parts of product whichcorresponded by nitrogen analysis to nonylbenzyldimethylamine.

The procedure was repeated with p-1,3,5,5-

8 tetramethylpentylbenzyl chloride and a similar product obtained,p-(1,3,5,5-tetramethylpentyl) benzyldimethylamine.

(c) The procedure of Example 14 (a) was followed with use of 23.8 partsof p-2-octylbenzyl chloride as the alkylbenzyl halide. The productobtained was (2-octylbenzyl)dimethylamine.

We claim:

1. -As new chemical substances, compounds of the formula CH /OH| CH;/CH: (D r o wherein X is a halogen of atomic weight between and 80, A isan alkylene group having a chain of two to four carbon atoms, and R. isan alkyl group of seven to nine carbon atoms.

2. As a new chemical compound, N,N,N',N- tetramethyl N,N'bis(octylbenzyl) butylene- 1,4-bis (ammonium chloride) 3. As a newchemical compound, N,N,N',N- tetramethyl N,N bis(octylbenzyl) butylene-1,4-bis(ammonium bromide).

4. As a new chemical compound, N,N',N',N'- tetramethyl N,N'bis(nonylbenzyl) butylene 1,4-bis (ammonium chloride) PETER L. DEBENNEVILLE. RICHARD W. GORMLY.

No references cited.

1. AS NEW CHEMICAL SUBSTANCES, COMPOUNDS OF THE FORMULA